1. Technical Field
This invention relates to an electrotransport agent delivery device and method having a reduced tendency to deliver extraneous and potentially toxic metal ions into the body. More specifically, this invention relates to a device for electrotransport delivery of a drug into the body, which device utilizes an electrical circuit without soldered electrical connections.
2. Background Art
The present invention concerns apparati for transdermal delivery of a therapeutic agent by electrotransport. The therapeutic agent or species to be delivered may be partially or completely charged and be delivered by electromigration (charged particle flow induced by an imposed electrical field); the agent or species may be completely uncharged (i.e., zero percent ionized) and be delivered by electroosmosis (flow of uncharged particles induced by an imposed electrical field); or the agent or species may be partly charged and be delivered by electromigration, by electroosmosis, or by a combination of these two processes. Electroosmosis has also been referred to as electrohydrokinesis, electroconvection, and electrically-induced osmosis. In general, electroosmosis of a therapeutic species into a tissue results from the migration of solvent, in which the species is contained, as a result of the application of electromotive force to the therapeutic species reservoir.
As used herein, the term "electrotransport" refers broadly to each of the following iontophoretic phenomena: (1) the delivery of charged drugs or agents by electromigration and/or electroosmosis; (2) the delivery of uncharged drugs or agents by the process of electroosmosis; and/or (3) the delivery of a mixture of charged and uncharged drugs or agents by electromigration and/or electroosmosis.
As used herein, the terms "agent" and "drug" are used interchangeably and are intended to have broad application and to refer to any therapeutically active substance that is delivered to a living organism to produce a desired, usually beneficial, effect. In general, this includes therapeutic agents in all of the major therapeutic areas including, but not limited to: anti-infectives such as antibiotic and antiviral agents; analgesics, including fentanyl, sufemanil, buprenorphine and analgesic combinations; anesthetics, anorexics; antiarthritics; antiasthmatic agents, such as terbutaline; anticonvulsants; antidepressants; antidiabetic agents; antidiarrheals; antihistamines; anti-inflammatory agents; antimigraine preparations; antimotion sickness preparations, such as scopolamine and ondansetron; antinauseants; antineoplastics; antiparkinson drugs; cardiostimulants, such as dobutamine; antipruritics; antipsychotics; antipyretics; antispasmodics, including gastrointestinal and urinary; anticholinergics; sympathomimetrics; xanthine derivatives; cardiovascular preparations, including calcium blockers, such as nifedipine; beta blockers; beta-agonists, such as salbutamol and ritodrine; antiarrythmics; antihypertensives, such as atenolol; ACE inhibitors, such as enalapril; diuretics; vasodilators, including general, coronary, peripheral and cerebral; central nervous system stimulants; cough and cold preparations; decongestants; diagnostics; hormones, such as parathyroid hormone; hypnotics; immunosuppressives; muscle relaxants; parasympatholytics; parasympathomimetrics; prostaglandins; proteins; peptides; psychostimulants; sedatives and tranquilizers.
The invention is also useful in active delivery of peptides, polypeptides, proteins and other macromolecules. These macromolecular substances typically have a molecular weight of at least 300 Daltons, and more typically have a molecular weight in the range 300-40,000 Daltons. Specific examples of peptides and proteins in this weight range include, without limitation: LHRH; LHRH analogs, such as buserelin, gonadorelin, nafarelin and leuprolide; GHRH; GHRF; insulin; insulotropin; heparin; calcitonin; octreotide; endorphin; TRH; NT-36 (chemical name: N.dbd.[[(s)- 4-oxo-2-azetidinyl]carbonyl]-L-histidyl-L-prolinamide), liprecin; pituitary hormones, such as HGH, HMG, HCG and desmopressin acetate; follicle luteoids; .alpha.ANF; growth factors, such as growth factor releasing factor (GFRF), .beta.MSH; somatostatin; bradykinin; somatotropin; platelet-derived growth factor; asparaginase; bleomycin sulfate; chymopapain; cholecystokinin; chorionic gonadotropin; corticotropin (ACTH); erythropoietin; epoprostenol (platelet aggregation inhibitor); glucagon; himlog; hyaluronidase; interferon;; intedeukin-1; intedeukin-2; menotropins (urofollitropin (FSH) and LH); oxytocin; streptokinase; tissue plasminogen activator; urokinase; vasopressin; desmopressin; ACTH analogs; ANP; ANP clearance inhibitors; angiotensin II antagonists; antidiuretic hormone agonists; antidiuretic hormone antagonists; bradykinin antagonists; CD4; ceredase; CSF's; enkephalins; FAB fragments; IgE peptide suppressors; IGF-1, neurotrophic factors; colony stimulating factors; parathyroid hormone and agonsists; parathyroid hormone antagonists; prostaglandin antagonists;pentigetide; protein C; protein S; renin inhibitors; thymosin alpha-1; thrombolytics; TNF; vaccines; vasopressin antagonists analogs; alpha-1 anti-trypsin (recombinant); and TGF-beta.
Iontophoretic devices for delivering ionized drugs through the skin have been known since the early 1900's. Deutsch, in U.K. Patent No. 410,009 (1934), describes an iontophoretic device that overcame one of the disadvantages of such early devices, namely that the patient needed to be immobilized near the source of electric current. The Deutsch device was powered by a galvanic cell formed from the electrodes and the material containing the drug to be transdermally delivered. The galvanic cell produced the current necessary for iontophoretically delivering the drug. This device thus allowed the patient to move around during iontophoretic drug delivery, and thus imposed substantially less interference with the patient's daily activities.
In presently known electrotransport devices, at least two electrodes are used. Both of these electrodes are disposed so as to be in intimate electrical contact with some portion of the skin of the body. One electrode, called the active or "donor" electrode, is the electrode from which the substance, agent, medicament, drug precursor or drug is delivered into the body through the skin by electrotransport. The other electrode, called the "counter" or return electrode, serves to close the electrical circuit through the body. In conjunction with the patient's skin contacted by the electrodes, the circuit is completed by connection of the electrodes to a source of electrical energy, such as a battery. For example, if an ionic substance to be driven into the body is positively charged, then the positive electrode (the anode) will be the active electrode and the negative electrode (the cathode) will serve to complete the circuit. If an ionic substance to be delivered is negatively charged, then the cathodic electrode will be the active electrode and the anodic electrode will be the counter electrode.
Furthermore, existing electrotransport devices have a reservoir or source of the beneficial agent or drug, preferably an ionized or ionizable species (or a precursor of such species) that is to be delivered or introduced into the body by electrotransport. Examples of such reservoirs or sources include: a pouch as described by Jacobsen in U.S. Pat. No. 4,250,878; a pre-formed gel body as disclosed in U.S. Pat. No. 4,382,529, issued to Webster; and a generally conical or domed molding disclosed in U.S. Pat. No. 4,722,726, issued to Sanderson et al. Such drug reservoirs are connected to the anode or the cathode of an electrotransport device to provide a fixed or renewable source of one or more desired species or agents.
Perhaps the most common use of electrotransport today is in diagnosing cystic fibrosis by delivering pilocarpine transdermally. Transdermal electrotransport delivery of pilocarpine stimulates sweat production, and the sweat is collected and is analyzed for its chloride ion content. Chloride ion concentration in excess of certain limits suggests the possible presence of the cystic fibrosis disease.
All electrotransport agent delivery devices utilize an electrical circuit to electrically connect the power source (e.g., a battery) to the electrodes. In very simple devices, such as those disclosed by Ariura et al. in U.S. Pat. No. 4,474,570, the "circuit" is merely an electrically conductive wire used to connect the battery to an electrode. Other devices use a variety of electrical components to control the amplitude, polarity, timing, waveform shape, etc. of the electric current supplied by the power source. See, for example, U.S. Pat. No. 5,047,007, issued to McNichols et al.
More recently, there has been an effort to develop miniaturized iontophoretic drug delivery devices which are adapted to be worn on the skin, unobtrusively and under a patient's clothing. The electrical components in such miniaturized iontophoretic drug delivery devices are also preferably miniaturized, and may be in the form of either integrated circuits (i.e., microchips) or small printed flexible circuits. Although printed circuits are desirable from a cost standpoint, there are potential problems with the use of conventional printed circuits when the circuits come into contact with the liquid solvent (usually water) used to solubilize the agents contained in the donor and counter electrode assemblies. For example, conventional printed circuits are formed by printing or otherwise depositing electrically conductive pathways on a flexible substrate, usually in the form of a polymer sheet. Electronic components, such as batteries, resistors, pulse generators, capacitors, etc., are then electrically connected, for example, by soldering to the printed or deposited electrically conductive pathways to form a complete circuit.
Presently, most flexible circuits are manufactured using a copper-coated polyimide or polyester sheet that is etched to remove the copper coating from pre-selected areas of the sheet. The copper-coated portions of the sheet remain after the etching process and define the desired circuit traces. Circuit components are usually soldered onto the circuit, using solder that contains lead, copper and other metals to promote good electrical contact.
This technology has certain associated problems when used in an electrotransport system. First, the circuits must undergo cleaning procedures, after etching and soldering, that may leave soluble (e.g., water soluble) chemical residues on the circuit that may be pharmaceutically undesirable or even toxic. Second, untreated copper circuit traces corrode over time, which limits the shelf life of the circuit and of any associated pharmaceutical electrotransport system. A common technique for suppressing the corrosion of copper circuit traces entails solder-coating the traces. Solder contains metals, such as lead, that are toxic and that can present a serious health hazard if delivered into the body. If the solder used in the electrical circuit inadvertently comes into contact with the liquid solvent contained in an electrode assembly (e.g., a drug solution in a donor electrode assembly, or an electrolyte salt solution in a counter electrode assembly) during operation of an associated electrotransport system, extraneous metal ions from the solder, such as copper and/or lead, can be inadvertently introduced into one or both of the electrode assemblies, and transported into the patient's body. This is particularly troublesome in electrotransport devices that are adapted to be worn and used over extended periods of time. Thus, there is a need for an electrotransport device that utilizes a flexible electrical circuit, which circuit has a lessened tendency to generate and introduce undesirable extraneous ions into the hydrated electrode assemblies. There is a further need for an electrotransport agent delivery device that utilizes a flexible electrical circuit, which circuit is substantially free of solder and other materials which can act as a source of undesirable extraneous ions.